A sodium salt of Loxoprofen (formal name: 2-[p-(2-oxocyclopentylmethyl)phenyl] propionic acid), otherwise known as Loxoprofen sodium, has excellent efficacy as a phenylpropionic acid type nonsteroidal anti-inflammatory agent and is widely used as a medicine for internal use under the trade name of "Loxonin."
By the way, Loxoprofen sodium is a prodrug. When orally administered, it is metabolized in the body into a trans-OH form (formal name: 2-[p-(trans-2-hydroxycyclopentylmethyl)phenyl] propionic acid), which exhibits excellent anti-inflammatory activities, as is known in the art [Matsuda et al. Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp. 263 to 266 (1983)]. An enzyme (a ketone-reducing enzyme) which is associated with this metabolism, mainly exists in the liver and kidney [Tanaka et al., Japanese Journal of Inflammation, Vol. 3, No. 2, Spring, pp. 151 to 155 (1983)], and the trans-OH form is known to exhibit inhibitory activity against cyclooxygenase, a prostaglandin producing enzyme, approximately 80 times as potently as Loxoprofen sodium [Matsuda et al. Japanese Journal of Inflammation, Vol. 2, No. 3, Summer, pp.263 to 266 (1983)]. Accordingly, it has been understood that Loxoprofen sodium must pass through the liver or kidney, where it is activated, before Loxoprofen sodium can exhibit its excellent anti-inflammatory analgesic activities.
Thus, when Loxoprofen sodium is used as an external formulation, it should not be treated in the same manner as anti-inflammatory analgesics, such as indomethacin, ibuprofen and ketoprofen, in case of which the drug itself provides a pharmacological effect.
However, hitherto, many patent applications have been filed for external formulations containing an anti-inflammatory analgesic as an active ingredient, in particular, for bases for external formulations, and some of them cite an anti-inflammatory analgesic as an example of an active ingredient that is contained in the formulation or that can be added to the base, and further, some of them cite Loxoprofen sodium as a specific example of the anti-inflammatory analgesic. Most of these applications, however, simply cite Loxoprofen as a mere example of the anti-inflammatory analgesic in the specification. Although some of these patent applications refer to crotamiton as an example of a solvent for active ingredients, which is one of the constituent features of the present application, none of the applications, in fact, does specifically disclose a formulation containing Loxoprofen and crotamiton.
On the other hand, in respect to Loxoprofen and its sodium salt, the external formulation are disclosed concretely in (1) Japanese Patent Application Laid Open No. Hei 4-99719, (2) Japanese Patent Application Laid Open No. Hei 8-165251, and (3) Japanese Patent Application Laid Open No. Sho 57-4919.
(1) is an invention on a novel base containing a certain type of fatty acid ester and polyhydric alcohols and intends to increase the speed at which an active ingredient permeates through the skin and a transdermal patch the base of which contains Loxoprofen sodium is prepared as an example there.
(2) discloses a specific solvent, [2-(2-methoxy-1-methylethyl)-5-methylcyclohexanol] and, an external formulation containing said solvent, a patch containing Loxoprofen is prepared as an example there, and its tackiness and safety to the skin are evaluated in the test examples. However, none of the patent applications refer to pharmacological effects of Loxoprofen sodium in the case where it is administered in the form of an external formulation.
In addition, when the present inventors prepared an external formulation of Loxoprofen sodium containing a fatty acid ester and a polyhydric alcohol in accordance with (1) and observed it with the passage of time, crystals of Loxoprofen were deposited. In general, when an external formulation of a certain compound is prepared, a solvent is added in order to avoid the crystallization and deposition of the active ingredient. The selection of an optimal solvent is an important element for the design of a formulation. Depending on the type of a selected solvent, there may occur a decreased release of the active ingredient from the base and a decreased transfer of it to the affected part because of the insufficient dissolution of the drug, thereby failing to provide sufficient therapeutical effects. In other words, a solvent that is optimal for a particular active ingredient cannot be expected to be also optimal for other active ingredients.
On the other hand, Japanese Patent Application Laid Open No. Sho 57-4919 (the above mentioned (3)) describes, in test examples, the pharmacological effects as external formulations of a solution of Loxoprofen in croton oil and of an ointment obtained by simply adding Loxoprofen sodium to Plastibase 50W. Croton oil, however, is a toxic substance which is used as an irritant and cocarcinogen in the research of cancer [THE MERCK INDEX, twelfth edition, pp. 2665] so that it is inappropriate to mix such a substance into a medicine. In addition, the efficacy of a formulation comprising a combination of Loxoprofen sodium and Plastibase 50W does not exhibit dosage dependence.